Role of Clostridium perfringens Enterotoxin on YAP Activation in Colonic Sessile Serrated Adenoma/ Polyps with Dysplasia.

• Material Type: 博士論文
• Title: Role of Clostridium perfringens Enterotoxin on YAP Activation in Colonic Sessile Serrated Adenoma/ Polyps with Dysplasia.
• Author/Editor: Fujiwara-Tani, Rina; Fujii, Kiyomu; Mori, Shiori; Kishi, Shingo; Sasaki, Takamitsu; Ohmori, Hitoshi; Nakashima, Chie; Kawahara, Isao; Nishiguchi, Yukiko; Mori, Takuya; Sho, Masayuki; Kondoh, Masuo; Luo, Yi; Kuniyasu, Hiroki
• Author Heading: Fujiwara-Tani, Rina; Fujii, Kiyomu; Mori, Shiori; Kishi, Shingo; Sasaki, Takamitsu; Ohmori, Hitoshi; Nakashima, Chie; Kawahara, Isao; Nishiguchi, Yukiko; Mori, Takuya; Sho, Masayuki; Kondoh, Masuo; Luo, Yi; Kuniyasu, Hiroki
• Publication, Distribution, etc.: MDPI
• Publication Date: 2020-05-28
• Publication Date (W3CDTF): 2020-05-28
• Alternative Title: 大腸 Sessile Serrated Adenoma/Polyps with Dysplasia における YAP 活性化に対する Clostridium perfringens のエンテロトキシンの役割
• Periodical title: International journal of molecular sciences
• No. or year of volume/issue: 21 11
• Volume: 21
• Issue: 11
• Pages: Article No.3840-
• ISSN (Periodical Title): ISSN : 1422-0067
• Degree grantor/type: 奈良県立医科大学
• Date Granted: 2022-03-15
• Dissertation Number: 甲第819号
• Degree Type: 博士（医学）
• Text Language Code: eng
• Subject Heading: clostridium perfringens enterotoxin; claudin-4; YAP; Hippo signal; SSA/P
• Target Audience: 一般
• Note (General): type:Thesis; Sessile serrated adenoma/polyp with dysplasia (SSA/P-D) is an SSA/P with cellular dysplasia and has a higher risk of progressing to colon carcinogenesis. Previously, we reported that tight junction impairment by Clostridium perfringens enterotoxin (CPE) leads to activation of the transcriptional co-activator yes-associated protein (YAP) in oral squamous cell carcinoma. Here, we investigated whether CPE activates YAP to promote the malignant progression of SSA/P. E-cadherin expression was lower in the 12 cases with SSA/P-D examined than that in normal mucosa, SSA/P, or tubular adenoma (TA). Furthermore, intracellular translocation of claudin-4 (CLDN4) and nuclear translocation of YAP were observed. The CPE gene was detected in DNA extracted from SSA/P-D lesions, but not in SSA/P or TA. Treatment of the rat intestinal epithelial cell line IEC6 with low-dose CPE resulted in intracellular translocation of CLDN4 to the cytoplasmic membrane. Cytoplasmic CLDN4 showed co-precipitation with transcriptional co-activator with PDZ-binding motif, zonula occludens (ZO)-1, large tumor suppressor, and mammalian Ste20-like. Additionally, YAP co-precipitated with ZO-2 under CPE treatment led to decreased YAP phosphorylation and nuclear translocation. YAP activation promoted increase in nuclear TEA domain family member level, expression of cyclin D1, snail, vimentin, CD44, NS and decrease in E-cadherin levels, thereby inducing stemness and epithelial-mesenchymal-transition (EMT). The Hippo complex with the incorporation of CLDN4 increased stability. Upon low-dose CPE treatment, HT29 cells with BRAFᵛ⁶⁰⁰ᴱ gene mutation showed increased growth, enhanced invasive potential, stemness, and induced EMT phenotype, whereas HCT116 cells, which carry KRASᴳ¹³ᴰ gene mutation, did not show such changes. In an examination of 10 colorectal cancers, an increase in EMT and stemness was observed in CPE (+) and BRAF mutation (+) cases. These findings suggest that C. perfringens might enhance the malignant transformation of SSA/P-D via YAP activation. Our findings further highlight the importance of controlling intestinal flora using probiotics or antibiotics.; 博士（医学）・甲第819号・令和4年3月15日; © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).; identifier:International journal of molecular sciences Vol.21 No.11 Article No.3840 (2020 May); identifier:14220067; identifier:http://ginmu.naramed-u.ac.jp/dspace/handle/10564/4002; identifier:International journal of molecular sciences, 21(11): Article No.3840
• Source: fulltext; http://ginmu.naramed-u.ac.jp/dspace/bitstream/10564/4002/1/01%e7%94%b2819%e6%9c%ac%e6%96%87%e3%81%ae%e8%a6%81%e6%97%a8.pdf; http://ginmu.naramed-u.ac.jp/dspace/bitstream/10564/4002/2/02%e7%94%b2819%e5%af%a9%e6%9f%bb%e8%a6%81%e6%97%a8.pdf; http://ginmu.naramed-u.ac.jp/dspace/bitstream/10564/4002/3/03%e7%94%b2819%e6%9c%ac%e6%96%87.pdf
• Access Restrictions: インターネット公開
• Related Material (DOI): 10.3390/ijms21113840
• Periodical Title (NCID): AA12038549; https://ci.nii.ac.jp/ncid/AA12038549
• Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）; https://irdb.nii.ac.jp
• Original Data Provider (Database): 奈良県立医科大学 : 奈良県立医科大学機関リポジトリ GINMU